Abstract 050: Diet quality, pathway-specific polygenic risk scores, and risk of type 2 diabetes among US men and women

Background: Healthy diets are associated with lower risk of type 2 diabetes (T2D) risk, but it is unclear if individuals with different genetic risks benefit from specific dietary strategies. Hypothesis: The associations between healthy dietary patterns and lower T2D risk may be modified by global and pathway-specific polygenic risk scores (PRS). Methods: We conducted prospective analyses in 40,609 participants from the Nurses’ Health Studies and Health Professionals Follow-Up Study, who were free of baseline diabetes, cardiovascular disease, and cancer, with up to 36 years of follow-up. Diet was assessed every 4 years via a food frequency questionnaire. We examined 6 recommendation-based and 2 mechanistic-based dietary patterns. A global PRS and 12 pathway-specific PRS denoting distinct T2D mechanisms were calculated. Cox regression was used to examine diet, PRS, and their interactions with T2D risk. Results: We identified a total of 4,760 T2D cases during the follow-up. Higher global PRS and 11 pathway-specific PRS, except the one related to bilirubin metabolism, significantly predicted higher T2D risk. In multivariable-adjusted analyses, all dietary indices indicating a lower dietary quality were associated with higher T2D risk (hazard ratios comparing extreme quintiles 1.06-2.21, P-trend <0.05/8). We found additive interactions between the Global PRS and the alternate Healthy Eating Index, healthy plant-based diet index, and proinflammatory and hyper-insulinemic diets, in relation to T2D risk (relative excess risk due to interaction 0.09 to 0.32, P-interaction ≤0.004; Figure ). PRS for beta-cell dysfunction and fat deposition-mediated insulin resistance also showed interactions with proinflammatory and hyper-insulinemic diets ( P-interaction ≤0.004; Figure ). Conclusions Healthy dietary patterns are associated with lower T2D risk across a wide genetic risk spectrum. Diets targeting inflammation and insulinemia may be particularly beneficial for those genetically predisposed to beta-cell dysfunction and fat deposition-mediated insulin resistance.